COPD is a complex lung disorder with distinct compartmental manifestations which challenge simplistic notions of single gene or single pathway causality. Whereas the airway findings of subepithelial fibrosis and fibroblast proliferation seem to reflect exuberant matrix deposition, the airspace findings of septal loss and cellular apoptosis conversely suggest matrix deficiency or resorption. One pathway that can negotiate matrix disturbances, inflammation and reduced cell survival is the TGFb cascade. The TGFb family of growth factors plays critical roles in tissue homeostasis, cell survival and differentiation. We present recent data showing that TGFb antagonism with angiotensin receptor blockade ameliorates CS-induced lung injury in animal models. The current proposal seeks to determine whether TGFb pathway is a viable therapeutic target for COPD and develop agents which can rationally target this pathway. In Aim 1, we subject genetically targeted animal models harboring compartmental deficiencies in TGFb signaling to chronic cigarette smoke exposure to determine the primary site of TGFb dysregulation in murine CS-induced emphysema. In Aim 2, we will test a small molecule antagonist of TGFb signaling that specifically inhibits the type I TGFbeta receptor (Alk5) for preclinical efficacy in an established animal model of CS induced emphysema. As proof of principle, we will also synthesize a nanoparticle formulation of an angiotensin receptor blocker, a class of agents that we have found improves lung histology in CS-exposed mice via TGFb inhibition, for optimal distal lung delivery. Finally, in Aim 3, utilizing a clinically validated methodology, we determine whether systemic and/or lung specific TGFbl levels are biomarkers of pharmacologic efficacy in COPD pts from two cohorts of patients: COPD patients being treated with Losartan, an angiotensin receptor blocker, in a pilot clinical trial and specimens provided by the LTRC repository of specimens from patients with COPD of varying severity. Upon completion, these studies will 1) identify the compartmental aspects of dysregulated TGFb signaling in COPD, 2) validate and explore novel antiTGFb therapies as rational approaches for the disorder and 3) establish whether serum or lung levels of TGFb ligands can be used as a pharmacologic biomarkers for clinical studies targeting this pathway. RELEVANCE (See instructions); COPD is common, costly and clinically burdensome. Although it is the fourth leading cause of death in the United States, there are no treatments that alter the natural history of this highly morbid disorder. In the current proposal, we perform a detailed evaluation of the TGFb pathway as a rational target for COPD treatment utilizing human materials, animal model systems and candidate therapeutic agents.